Pyrethrins

The pyrethrins are valuable insecticidal components of pyrethrum flowers, Chrysanthemum cinerariaefolium (= Tanacetum cinerariifolium) (Compositae/Asteraceae). The flowers are harvested just before they are fully expanded, and usually processed to an extract. Pyrethrum cultivation is conducted in East Africa, especially Kenya, and more recently in Ecuador and Australia. The natural pyrethrins are used as a constituent of insect sprays for household use and as post-harvest insecticides, having a rapid action on the nervous system of insects, whilst being biodegradable and non-toxic to mammals, though they are toxic to fish and amphibians. This biodegradation, initiated by air and light, means few insects develop resistance to the pyrethrins, but it does limit the lifetime of the insecticide under normal conditions to just a few hours.

The flowers may contain 0.7-2% of pyrethrins, representing about 25-50% of the extract. A typical pyrethrin extract contains pyrethrin I (35%), pyrethrin II (32%), cinerin I (10%), cinerin II (14%), jasmolin I (5%), and jasmolin II (4%), which structures represent esters of chrysanthemic acid or pyrethric acid with the alcohols pyrethrolone, cinerolone, and jasmolone (Figure 5.18). Pyrethrin I is the most insecticidal component, with pyrethrin II providing much of the rapid knock-down (paralysing) effect. A wide range of synthetic pyrethroid analogues, e.g. bioresmethrin, tetramethrin, phenothrin, permethrin, and cypermethrin (Figure 5.18), have been developed, which have increased lifetimes up to several days and greater toxicity towards insects. These materials have become widely used household and agricultural insecticides. Tetramethrin, bioresmethrin, and phenothrin are all esters of chrysanthemic acid but with a modified alcohol portion, providing improvements in knock-down effect and in insecticidal activity. Replacement of the terminal methyls of chrysanthemic acid with chlorine atoms, e.g. permethrin, conferred greater stability towards air and light, and opened up the use of pyrethroids in agriculture. Inclusion of a cyano group in the alcohol portion as in cypermethrin improved insecticidal activity several-fold. Modern pyrethroids now have insecticidal activities over a thousand times that of pyrethrin I, whilst maintaining extremely low mammalian toxicity. Permethrin and phenothrin are employed against skin parasites such as head lice.

to a six-membered oxygen heterocycle, e.g. nepetalactone from catmint Nepeta cataria (Labiatae/Lamiaceae), a powerful attractant and stimulant for cats. The iridoid system arises from geraniol by a type of folding (Figure 5.22) which is different from that already encountered with monoterpenoids, and also different is the lack of phosphorylated intermediates and subsequent carbocation mechanism in its formation. The fundamental cyclization to iridodial is formulated as attack of hydride on the dialdehyde, produced by a series of hydroxylation and oxidation reactions on geraniol. Further oxidation gives iridotrial, in which hemiacetal formation then leads to production of the heterocyclic ring. In iridotrial, there is an equal chance that the original methyls from the head of geraniol end up as iridane iridane

nepetalactone

nepetalactone iridoid iridoid iridoid

Figure 5.21

secoiridoid secoiridoid a a

secoiridoid the aldehyde or in the heterocyclic ring. A large number of iridoids are found as glycosides, e.g. loganin, glycosylation effectively transforming the

hemiacetal linkage into an acetal. The pathway to loganin involves, in addition, a sequence of reactions in which the remaining aldehyde group is oxidized to the acid and methylated, giving deoxyloganin, and the final step is a hydroxylation reaction. Loganin is a key intermediate in the biosynthesis of many other iridoid structures, and also features in the pathway to a range of complex terpenoid indole alkaloids (see page 350) and tetrahydroisoquinoline alkaloids (see page 343). Fundamental in this further metabolism is cleavage of the simple monoterpene skeleton still recognizable in loganin to give secologanin, representative of the secoiridoids (Figure 5.21). This is catalysed by a cytochrome P-450-dependent mono-oxygenase, and a free radical mechanism is proposed in Figure 5.22. Secologanin now contains a free aldehyde group, together with further aldehyde and enol groups, these latter two fixed as an acetal by the presence of the glucose. As we shall see with some of the complex alkaloids, these functionalities can be released again by hydrolysing off the glucose and reopening the hemiacetal linkage. Gentiopicroside via hydroxylation cyclization formulated as initiated by electrophilic addition utilizing the unsaturated carbonyl, terminated by addition of hydride; the Schiff base-assisted mechanism Q shown below is more realistic via hydroxylation

Mechanism Gentiopicroside

Enz hemiacetal formation

CHO iridodial (keto form)

HNC @ Enz formation of alkene and ring cleavage H

CHO iridodial (keto form)

hemiacetal formation

iridodial (enol form)

iridodial (hemiacetal form)

iridodial (enol form)

iridodial (hemiacetal form)

OHC' "CHO iridotrial (keto form)

hemiacetal formation

OHC' "CHO iridotrial (keto form)

H OHC

H OHC

iridotrial (hemiacetal form)

iridotrial (hemiacetal form)

MeO2C

formation of alkene and ring cleavage H

MeO2C

Enz—Fe oxidation

O^ h leading to radical

I oxidation of aldehyde to acid J glucosylation I esterification

MeO2C

Enz—Fe oxidation

MeO2C

NAD2PH OGlc

MeO2C

„OGlc deoxyloganin

„OGlc loganin

MeO2C '

deoxyloganin glucosylation has now transformed the hemiacetal into an acetal

MeO2C

MeO2C

MeO2C

MeO2C

MeO2C

„OGlc secologanin

„OGlc tryptamine terpenoid indole alkaloids secologanin hydrolysis of ester; formation of enol CHO ^ tautomer

,OGlc

MeO2C

,OGlc

OH HO2C

allylic isomerization

,OGlc

OH HO2C

lactone formation

OH HO2C

lactone formation

OH HO2C

gentiopicroside

secologanin gentiopicroside

Figure 5.23

(Figure 5.23) is another example of a secoiridoid, and is found in Gentian root (Gentiana lutea; Gentianaceae), contributing to the bitter taste of this herbal drug. Its relationship to secologanin is suggested in Figure 5.23. The alkaloid gentianine (see page 386) is also found in Gentian root, and represents a nitrogen analogue of the secoiridoids, in which the pyran oxygen has been replaced by nitrogen.

A range of epoxyiridoid esters has been identified in the drug valerian* (Valeriana officinalis; Valeri-anaceae). These materials, responsible for the sedative activity of the crude drug, are termed valepo-triates. Valtrate (Figure 5.24) is a typical example, and illustrates the structural relationship to loganin, though these compounds contain additional ester functions, frequently isovaleryl. The hemiacetal is now fixed as an ester, rather than as a glycoside.

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